Platelet aggregation on a blood vessel is induced by several factors, e.g., collagen, adenosine diphosphate (ADP), thrombin, epinephrine, ristocetin and arachidonic acid. For instance, when epithelial cells of a blood vessel are damaged, collagen underneath the epithelial cells is exposed to blood stream and activates platelets. The activation of platelets triggers a cascade of reactions resulting in a thrombogenesis and platelet aggregation on the blood vessel, which may cause serious circulatory diseases, e.g., thrombosis, atherosclerosis, cerebral stroke and coronary artery thromboembolism.
Hitherto, various drugs, e.g., thromboxane A2 inhibitor, PGG/H synthase inhibitor, thromoxane synthase inhibitor, thromboxane A2 receptor antagonist, ticlopidine, GP Hb-IHa inhibitor and serotonin antagonist, have been developed in order to prevent such platelet aggregation. However, these drugs have shown various undesirable side effects on the internal organs, and hemorrhagenic properties.
Ticlopidine and analogues thereof, e.g., clopidogrel, selectively inhibit the ADP-induced platelet aggregation in vivo and are known to be effective in the treatment of a transient ischemic cerebral stroke and peripheral arterial or ischemic heart disease(Hass, W. K. et al., N. Engl. J. Med., 21, 501(1989); and Easton, J. D., Drugs, 42, 39(1991)). However, these drugs have been reported to have such undesirable side effects as myelosuppression, increase of total cholesterol level, diarrhea, eruption and neutropenia((McTavish, E. et al., 2Drugs, 40, 238(1990)); Hass, W. K. et al., supra; and Dunn C. D. R., Scrip. Reports, Stroke: Trends, Treatments and Markets, PJB Publications Ltd. pp133-139(1995)).
Accordingly, there has continued to exist a need to develop a platelet aggregation inhibitor having a highly selective inhibitory activity on the collagen-induced platelet aggregation and yet without incurring adverse side effects.
It is known that the flavonoids extracted from citrus peel, e.g., naringin, naringenin, hesperidin and hesperetin, have activities in improving lipid metabolism to prevent cardio-circulatory diseases, as well as anticancer and antiviral activities. In particular, it has been reported that both hesperidin and hesperetin have capillary-enhancing, permeability-reducing, anti-inflammation, anti-viral, and blood pressure- and cholesterol-lowering activities(Meyer, O. C., Angiology, 45, 579-584(1994); Struckmann, J. R. et al., Angiol., 45, 419-428(1994); Matsubara, Y. et al., Japan Organic Synthesis Chem. Association Journal, 52, 318-327(1994. March); Galati, E. M. et al., Farmaco., 51(3), 219-221(1996, March); Monforte, M. T. et al., Farmaco., 50(9), 595-599(1995, September); JP 95-86929; JP 95-86930; Galati, E. M. et al., Farmaco., 40(11), 709-712(1994, November); and Emim, J. A. et al., J. Pharm. Pharmacol., 46(2), 118-122(1994)). Further, it has been reported that both naringin and naringenin have anti-cancer, anti-ulcer, and cholesterol-lowering activities(Monforte, M. T. et al., Farmaco., 50(9), 595-599(1995, September); JP 95-86929; JP 95-86930; Felicia, V. et al., Nutr. Cancer, 26, 167-181(1996); EP 0352147 A2(1990.1.24); and Martin, M. J. et al., Parmacol., 49, 144-150(1994)).
Recently, it has also been reported that naringenin inhibits an arachidonic acid-induced platelet aggregation(Corcazier, E. et al., Biochimica Biophysica Acta, 835, 315-321(1985)).
However, there has been no report on the selective inhibitory activity of flavonoids derived from citrus peels on a collagen-induced platelet aggregation.